In the present invention, terms such as transdermal patch, transdermal absorption patch, transdermal administration patch etc. represent solid preparations (solidified preparations) of transdermal drug delivery systems for delivering drugs through the skin.
Pain is recognized by nociceptors and other neural cells associated with pain inducing pathways by responding to stimuli and sending signals via the spinal cord to the brain. Fentanyl and its derivatives are opioids and exhibit analgesic activity by binding to opiate receptors of spinal cord and inhibiting release of neurotransmitters, thereby preventing pain signals from being delivered to spinal cord neurons. Opioids may be effectively used for all kinds of pain relief from moderate to severe pain due to their efficacy and advantages such as convenient titration and risk-to-benefit ratio, contrary to NSAIDs having a ceiling effect in analgesic activity.
Fentanyl is suited to transdermal administration. When fentanyl is administered transdermally, fentanyl may be administered by simple attachment, and may have merits in that fentanyl is not passed through liver first-pass metabolism, and has improved patient convenience and medication compliance, constant analgesic activity, lessened nursing effort, reduced sleep interference etc. Fentanyl preparations administered transdermally may be used particularly in cancer patients. When body temperature is increased due to cancer, reaction time of fentanyl may be shortened due to increased absorption amount from subcutaneous tissues.
Examples of fentanyl transdermal preparations that are already commercially available include Durogesic (Janssen), Durogesic D-trans patch (Janssen), Fentanyl Transdermal System CII (Mylan, Teva, Watson), Fenstud (Rusan) etc. These preparations, aside from Durogesic and Durogesic D-trans patches, are all generic medicines. Durogesic is a reservoir type and is designed such that fentanyl is mixed and dissolved in a liquid drug-containing layer consisting of ethanol and water. This reservoir type transdermal administration preparation comprises a backing layer, a reservoir layer of gel containing a drug and ethanol as a transdermal absorption enhancer, a membrane layer to control release rate, an adhesive layer and a detachable layer. Accordingly, the reservoir type transdermal preparation has merits that the release rate of drugs is easily controlled and skin permeation is accelerated. However, owing to irritation caused by ethanol used as a skin permeation accelerator, one may suffer side effects such as skin irritation or the like when the preparation is used for long time, for example, for three days or so. In addition, the preparation has disadvantages in that production of the preparation requires considerably complicated production processes since the preparation comprises several layers, the preparation has a bad sense of skin attachment and efficacy of the preparation is exhibited only after 12 hours or more (lag time). Further, if the reservoir of the reservoir type fentanyl transdermal preparation leaks, there are disadvantages in that the content in the active compound-containing reservoir comes into contact with the skin over wide area, and thus the active compound is absorbed in an excessive dose amount. Especially, when fentanyl and its derivatives are administered to a human in an excessive amount, it is particularly dangerous since rapid respiratory decline may occur, possibly resulting in death (Clinical Pharmacokinetics. 2000, 38(1), 59-89).
In order to overcome such disadvantages, matrix type monolithic patches have been developed using acrylic adhesives. These preparations have achieved some improvement in their performance such as stable delivery of drugs, reduction in skin irritation by ethanol etc. However, these preparations still have problems in that detachment by moisture and sweat, and skin irritation due to adhesiveness of the monolithic patches are not completely solved.
Further, in an attempt to shorten lag time, patches to induce rapid release of drugs have been developed using silicone type or rubber type adhesives having a fast spread rate and low fentanyl solubility. As silicone type adhesives, matrix type fentanyl patches using amine-resistant polydimethyl siloxane have been developed. As rubber type adhesives, an adhesive-base has been prepared by mixing high molecular weight and low molecular weight polyisobutylenes (PIB), or matrix type fentanyl patches including styrene block copolymer styrene-isoprene-styrene (SIS) and polyisobutylene (PIB) have been designed. These patches have the effects that the skin permeation rate of drugs is increased, thereby decreasing patch area. Since high molecular weight polyisobutylenes constituting the matrix of preparations are excessively hydrophobic, the patches still have problems of detachment due to sweat or moisture.
When a preparation is prepared by including a matrix layer formed by two adjacent adhesive polymers layers having different fentanyl solubilities, a certain amount of fentanyl is rapidly released from the adhesive polymer layer having a low fentanyl solubility at an early stage of administration to shorten time for reaching an effective blood concentration, thereby moving up the onset time of analgesic effects. When a predetermined time has passed, a drug may be released from the adhesive polymer layer having a high fentanyl solubility sufficient to maintain the effective blood concentration, thereby maintaining long-term analgesic effects. However, in order to produce the preparation, two kinds of drug-containing adhesive solutions should be separately prepared. Namely, one drug-containing adhesive solution is applied to a backing layer, while the other drug-containing adhesive solution is applied to a detachable layer, followed by drying. The two drug-containing adhesive layers should be accurately placed facing each other without overlapping. Subsequently, in order to prepare the preparation, the opposite drug-containing adhesive layers should be accurately cut so that the preparation has a certain area of the two drug-containing adhesive layers. In this context, the process for producing the preparation is complicated. Additionally, the loss rate of fentanyl occurring during the process is very high.
Therefore, there is a need for a new fentanyl transdermal patch which can be prepared simply, deliver fentanyl constantly for long time (three days), maintain long term skin attachment and does not have side effects of skin irritation.